Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (nitrogen monoxide, NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells.
Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are extracellular arginine, 17β-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349) were able to obtain a marked increase in eNOS by means of exercise training and the increase in shear stress associated therewith.
Whether regulation at the post-transcriptional level is relevant in vivo, has not been unambiguously proven. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease.
On the other hand, the significance of the upregulation of the eNOS protein is scientifically accepted. Thus, there are findings which show that the protective properties of the HMG-CoA reductase inhibitor simvastatin can be attributed, besides to the lipid lowering, also in part to an increase in eNOS expression in vivo (Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880). It is additionally known that single point mutations in the 5′-flanking region of the eNOS gene (“eNOS promoter”), and the reduction in the rate of eNOS gene transcription associated therewith, in the Japanese population is associated with an increase in the risk of coronary spasms (Nakayama et al., Circulation 99 (1999) 2864).
The current assumption therefore is that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in very early stages of a wide variety of cardiovascular disorders it is possible for a dysfunction of this type in the endothelium lining the blood vessels to lead to a deficiency of bioactive NO, which is manifested as the disorder progresses in the form of measurable pathophysiological and morphological changes. Thus, critical steps in early atherogenesis are speeded up by a decrease in endothelial NO release, such as, for example, the oxidation of low density lipoproteins, the recruitment and deposition of monocytes in the intima of vessels, and the proliferation of intimal cells. A consequence of atherogenesis is the formation of plaques on the inside of the blood vessels, which may in turn lead, through a diminution in the shear stress, to a further decrease in endothelial NO release and a further deterioration in the pathology. Since endothelial NO is also a vasodilator, a decrease thereof frequently also leads to hypertension which may, as an independent risk factor, cause further organ damage.
The aim of a therapeutic approach to the treatment of these disorders must accordingly be to interrupt this chain of events by increasing the endothelial NO expression. Gene transfer experiments which lead in vitro to overexpression of NO synthase in previously damaged vessels are in fact able to counteract the described processes and are thus evidence of the correctness of this approach (Varenne et al., Hum. Gene Ther. 11 (2000) 1329).
Some low molecular weight compounds which, in cell cultures, may lead to a direct effect on eNOS transcription and expression are disclosed in the literature. For the statins, as has already been mentioned, it has been possible to show such an increase in eNOS in vivo as a side effect. In view of the known range of side effects of this class of substances, however, it is unclear how far use of this effect can be made in a toxicologically unproblematic dose. Liao et al. claim in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents which influence the organization of the actin cytoskeleton for increasing eNOS in endothelial cells and for the therapy of various disorders such as, for example, strokes or pulmonary hypertension without, however, indicating a specific way of achieving this. Certain amide derivatives which upregulate the expression of endothelial NO synthase, in particular N-cycloalkyl amides in which the cycloalkyl ring is fused to a benzene ring or a heteroaromatic ring, have been described in WO 02/064146, WO 02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372 and WO 2004/014842. Certain triaza- and tetraaza-anthracenedione derivatives which upregulate the expression of endothelial NO synthase have been described in WO 2004/094425. There still exists a need for further compounds which upregulate the expression of endothelial NO synthase and have a favorable property profile and are useful as pharmaceuticals for the treatment of various diseases such as atherosclerosis, coronary artery disease or cardiac insufficiency, for example. Surprisingly it has now been found that the compounds of the formula I are modulators of the transcription of endothelial NO synthase and in particular stimulate, or upregulate, the expression of eNOS, and are useful for the treatment of various diseases such as the mentioned cardiovascular disorders.
Certain heteroarylcyclopropanecarboxamides, in which an aryl or heteroaryl group is linked to the heteroaryl substituent on the cyclopropane ring and which are structurally related to formula I, have already been described. For example, in EP 0253502 N-disubstituted 2-heteroarylcyclopropanecarboxamides are generically disclosed which are intermediates for the preparation of fungicides and in which the heteroaryl group is an unsubstituted or substituted furanyl, thiophenyl or pyrrolyl group and the two substituents on the nitrogen atom of the amide group are (C1-C4)-alkyl or together with the nitrogen atom form an unsubstituted or substituted heterocyclic ring which optionally contains an additional heteroatom. In WO 2004/050643 inhibitors of HIV reverse transcriptase are described which comprise two (hetero)aryl groups and which can contain, among others, a cyclopropanecarboxamide moiety, for example the compound N-(2-nitrophenyl)-2-(1-(naphthalen-1-yl)-1-H-tetrazol-5-yl))-cyclopropanecarboxamide. In WO 96/374691-benzylindolyl derivatives, including the compound 3-(2-(1-(4-bromobenzyl)-5-methoxy-2-methyl-indol-3-yl)-cyclopropanecarbonyl)-4-isopropyl-2-oxazolidinone, are described which are inhibitors of cyclooxygenase 2 useful for the treatment of inflammatory diseases. In WO 93/21153 indole-2-carboxylic acid derivatives are described which are excitatory amino acid antagonists useful for the treatment of neurodegenerative diseases and other diseases, including the compounds 3-(2-phenylcarbamoyl-cyclopropyl)-4,6-dichloro-indole-2-carboxylic acid and the ethyl ester thereof. In EP 0436199 cyclopropyl derivatives are described which comprise an N-hydroxy moiety, for example an N-hydroxyurea or N-hydroxycarboxamide moiety, and which are lipoxygenase inhibitors useful for the treatment of inflammatory diseases, as well as respective compounds comprising an N-alkyloxy moiety, for example the compounds 2-(5-(4-fluorophenoxy)-furan-2-yl)-N-methoxy-N-methyl-cyclopropanecarboxamide and 2-(2-(4-chlorophenoxy)-thiazol-5-yl)-N-methoxy-N-methyl-cyclopropanecarboxamide. Also the imidazolyl derivatives described in US 2005/0070588, including the compound 2-(5-(4-methoxyphenyl)-2-phenyl-1H-imidazol-4-yl)-N-(4-pentyl-phenyl)-cyclopropanecarboxamide, are inhibitors of lipoxygenase. U.S. Pat. No. 6,649,638 and WO 2004/016592, which relate to inhibitors of protein prenylation useful for the treatment of cancer and other diseases, disclose the compound N-(1-carbamoyl-2-phenyl-ethyl)-2-(2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-2H-pyrazol-3-yl)-cyclopropanecarboxamide. In WO 96/38141 and WO 01/81317 imidazolylcyclopropanecarboxamides are disclosed which carry a triphenylmethyl group on the nitrogen atom of the imidazolyl ring and which are intermediates in the preparation of histamine H3 receptor antagonists. However, the compounds specifically disclosed in these references are structurally distinguished from the compounds which are a subject of the present invention as compounds per se, and a stimulating effect of known heteroarylcyclopropanecarboxamides on the transcription or the expression of eNOS and their use in the treatment of diseases which is based on such effect, has not been described.